DCEG has a long and distinguished history of investigating the relationship between treatments administered to patients to control an initial cancer, and the risk of subsequently developing a second cancer. This represents a unique observational situation in which one can study the consequences of human exposure to well-defined chemical carcinogens and to ionizing radiation. We are now moving these studies into the genetic arena, by investigating the relationship between common polymorphisms in genes affecting the bioavailability of chemical carcinogens as well as DNA repair, and various outcomes of clinical interest. Such studies could identify population sub-groups which are at particular risk of second cancers, thrombotic events, acute myelosuppression, response to treatment or even survival. The potential also exists to identify genetic variants which may reduce the risk of adverse outcomes. Information of this kind could have a significant impact on clinical decision-making. (a) CGB's first pharmacogenetics project targets genetic polymorphisms in the genes related to tamoxifen and estrogen bioavailability and the risk of developing invasive breast cancer as a result of exposure to tamoxifen. Clinical trials have demonstrated that women exposed to tamoxifen are at increased risk of endometrial cancer, DVT, PE as well as stroke, and at decreased risk of developing breast cancer. In general terms, these differences have been attributed to tissue specific variations in whether tamoxifen acts as an estrogen agonist or an estrogen antagonist. We hypothesize that genetic variants (single nucleotide polymorphisms; "SNPs") in the genes which affect tamoxifen and/or estrogen metabolism may identify sub-groups of women who are more or less likely to benefit from the administration of tamoxifen. The first phase of this project is targeting the women who participated in NSABP's Tamoxifen Breast Cancer Prevention Trial ("P1"), with invasive breast cancer the first outcome to be investigated. A "case-only" study design has been chosen. Genotyping has been completed for the 40 polymorphisms selected for study is complete, and data analysis has entered its final stages. A manuscript should be complete early in 2007. Subsequent phases of this project may include: (a) analysis of the non-invasive breast cancers which developed in P1 subjects; (b) analysis of the endometrial neoplasms from this same study; and (c) genotyping of a random sample of the entire P1 cohort, to permit seeking evidence of a major effect for candidate genes, and to obtain the absolute risk estimates required (if evidence of a gene-tamoxifen interaction is found) to apply these findings clinically.(b) The second major study within this program area is an analysis of genetic polymorphisms in genes which are part of the IGF1 signaling pathway, and serum levels of IGF1, IGF2 and IGF-BP3, as risk factors for advanced colorectal adenoma. Elevated levels of IGF1, a cytokine with both mitogenic and anti-apoptotic effects, have been associated with increased risks of a variety of different cancers, including premenopausal breast, colon, prostate and lung cancer. In collaboration with the Core Genotyping Facility and the Office of the Director, Epidemiology & Biostatistics Program, genetic variations in these genes and circulating serum levels of these three peptives are being systematically identified and then studied as determinants of neoplasm risk among participants of the Prostate, Lung, Colon and Ovarian Cancer (PLCO)screening trial. The first phase has targeted 800 PLCO participants who were found to have advanced adenomatous polyps at the time of their baseline colonscopy, and 800 polyp-free controls. Sixty (60) single nucleotide polymorphisms (SNPs) in eight of the IGF1 signaling pathway genes are being studied as modifiers of adenoma risk.